Lyons began starring in the NBC medical drama ER as Dr. Simon Brenner, making his first appearance in season 14, episode 14 titled "Owner of a Broken Heart" which aired on 10 April 2008, though he was credited as a special guest star. When the show's 15th and final season premiere titled "Life After Death" aired on 25 September 2008, Lyons was added to the main cast. Lyons played this role until the show ended with the two-hour series finale, "And in the End...", which aired 2 April 2009.

In 2009, Lyons starred in the TV movieA Model Daughter: The Killing of Caroline Byrne.

In January 2011, Lyons starred as the titular role in the NBCsuperhero drama The Cape until the show was cancelled in March that same year after ten episodes.[2]

Lyons starred in the NBCpost-apocalyptic drama Revolution, which ran for two seasons from 17 September 2012 to 21 May 2014 as Sebastian "Bas" Monroe, a former US Marine Corps sergeant who served alongside Billy Burke's character Miles Matheson, founded the Monroe Republic, and became its President and later General of its Militia.[3]